In this application, entitled: NF: from animal models to therapeutics, we are requesting funds for continued support of the NF Center. We build on our preceding success in exploiting animal models to gain novel insight into tumor etiology and revealing the mast cell as a therapeutic target that is now in clinical trials. The Center supports a series of highly interactive and multidisciplinary studies aimed at (1) delineating the mechanisms underlying the two most common tumors in NF1: dermal and plexiform neurofibromas and (2) dissecting the unknown functions of neurofibromin in regulating adult endothelial and vascular smooth muscle function - two cell lineages critical for establishment of the tumor vasculature in neurofibromas, and in the development of NF1 vasculopathies. The Center is organized into a small Administrative Core, a Transgenic/Animal Core, and four Projects. The Transgenic/Animal Core (PI, Luis F. Parada) is responsible for breeding transgenic and knockout mice, genotyping, and for developing or importing additional mouse strains. Project 1 (PI, Luis F. Parada) is a continuation of a productive effort to study the molecular and cellular mechanisms by which NF1 mutation engenders plexiform neurofibromas and malignant peripheral nerve sheath tumors. Project 2 (PI, D. Wade Clapp) focuses on the signaling mechanisms that promote interplay between Nf1-/- Schwann cells and different heterozygous cell lineages identified in the tumor microenvironment in neurofibroma development and targeting these cell-cell interactions with FDA-approved therapeutics. Project 2 will also utilize human cells isolated from NF1 patients to verify that the observations in the murine model are faithfully recapitulated in the human system as a preclinical platform to identify therapeutic targets within the neurofibroma microenvironment. Project 3 (PI, David Ingram) will study the role of Nf1 in controlling endothelial and vascular smooth muscle/pericyte function. Project 4 (PI, Lu Q. Le) will investigate the etiology of dermal neurofibromas in mouse and proposes a clinical trial for treatment of human patients. Project 4 also proposes the establishment of a comprehensive NF1 clinic. Together, the proposed program of research promises to contribute to a better understanding of NF1-associated tumorigenesis at the molecular, cellular, and systems levels.